Project description:ImportanceControl of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.ObjectiveTo evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.Design, setting, and participantsTwenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.InterventionsParticipants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).Main outcomes and measuresHumoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.ResultsTwenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.Conclusion and relevanceIn this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.Trial registrationClinicalTrials.gov Identifier: NCT04436276.

Project description:ObjectiveTo assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa and to compare these rates with those observed in the general population.DesignOpen label, single arm, phase 3B study.SettingSisonke study, South Africa, 17 February to 15 June 2021.ParticipantsThe Sisonke cohort of 477 234 healthcare workers, aged ≥18 years, who received one dose of the Ad26.COV2.S vaccine.Main outcome measuresObserved rates of venous arterial thromboembolism and vaccine induced immune thrombocytopenia and thrombosis in individuals who were vaccinated, compared with expected rates, based on age and sex specific background rates from the Clinical Practice Research Datalink GOLD database (database of longitudinal routinely collected electronic health records from UK primary care practices using Vision general practice patient management software).ResultsMost of the study participants were women (74.9%) and median age was 42 years (interquartile range 33-51). Twenty nine (30.6 per 100 000 person years, 95% confidence interval 20.5 to 44.0) vascular thrombotic events occurred at a median of 14 days (7-29) after vaccination. Of these 29 participants, 93.1% were women, median age 46 (37-55) years, and 51.7% had comorbidities. The observed to expected ratios for cerebral venous sinus thrombosis with thrombocytopenia and pulmonary embolism with thrombocytopenia were 10.6 (95% confidence interval 0.3 to 58.8) and 1.2 (0.1 to 6.5), respectively. Because of the small number of adverse events and wide confidence intervals, no conclusions were drawn between these estimates and the expected incidence rates in the population.ConclusionsVaccine induced immune thrombocytopenia and thrombosis after one dose of the Ad26.COV2.S vaccine was found in only a few patients in this South African population of healthcare workers. These findings are reassuring if considered in terms of the beneficial effects of vaccination against covid-19 disease. These data support the continued use of this vaccine, but surveillance is recommended to identify other incidences of venous and arterial thromboembolism and to improve confidence in the data estimates.Trial registrationClinicalTrials.gov NCT04838795.

Project description:BackgroundThe Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear.MethodsIn this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting.ResultsHomologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration.ConclusionsThe Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

Project description:BackgroundReal-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data.Methods and findingsIn this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting.ConclusionsWe observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting.Trial registrationClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Project description:BackgroundThe Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.MethodsIn an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.ResultsThe per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).ConclusionsA single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Project description:BackgroundWe aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic.MethodsIn the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual.FindingsBetween Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]).InterpretationThe single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally.FundingNational Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

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Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study.

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